WO1999018970A1 - Medicaments a action preventive et remedes contre les troubles circulatoires ophtalmiques - Google Patents

Medicaments a action preventive et remedes contre les troubles circulatoires ophtalmiques Download PDF

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Publication number
WO1999018970A1
WO1999018970A1 PCT/JP1998/004599 JP9804599W WO9918970A1 WO 1999018970 A1 WO1999018970 A1 WO 1999018970A1 JP 9804599 W JP9804599 W JP 9804599W WO 9918970 A1 WO9918970 A1 WO 9918970A1
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group
ocular
retinal
methyl
preventing
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PCT/JP1998/004599
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English (en)
Japanese (ja)
Inventor
Takahiro Ogawa
Noriko Watanabe
Mitsunori Waki
Takashi Nakano
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Senju Pharmaceutical Co., Ltd.
Asahi Glass Co., Ltd.
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Application filed by Senju Pharmaceutical Co., Ltd., Asahi Glass Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO1999018970A1 publication Critical patent/WO1999018970A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to an agent for preventing and improving ocular circulation disorders. More specifically, the present invention relates to a prophylactic and / or ameliorating agent for ocular circulatory dysfunction, comprising a certain prostaglandin I 2 (PGI 2 ) derivative as an active ingredient.
  • PGI 2 prostaglandin I 2
  • the ophthalmic artery enters the orbit and branches into the central retinal artery, lacrimal artery, posterior ciliary artery, and pre-ciliary artery, and the central retinal vein and vortex vein From the eye and out of the eye through the eye vein.
  • the anterior ciliary artery leads to the vasculature such as the choroid, optic disc, iris, and ciliary body.
  • retinitis pigmentosa especially normotensive or hypotensive glaucoma
  • macular degeneration especially normotensive or hypotensive glaucoma
  • ischemic optic neuropathy especially retinitis pigmentosa
  • choroidal disease secondary to iridocyclitis retinitis pigmentosa
  • retinal choroidal disease especially myopia is induced by this.
  • endothelin (hereinafter also referred to as “ET-1”), thrompoxane A2, and angiotensin are among the various physiologically active substances produced by vascular endothelial cells.
  • ET-1 endothelin
  • thrompoxane A2 thrompoxane A2
  • angiotensin are among the various physiologically active substances produced by vascular endothelial cells.
  • ⁇ and in vivo amines dopamine, epinephrine, serotonin, etc.
  • changes in ocular blood flow due to biologically active substances are species-specific, individual-specific, eye-specific.
  • There is a large difference between tissues, etc. and an ocular circulation measurement method is also under development, and at present it has not been clarified yet.
  • microcirculation-improving agents such as vitamin E preparations such as tocoprol nicotinate and pentoxifylline and various steroids is performed.
  • the effect of improving ocular circulation is not enough, and side effects such as lowering blood pressure and gastrointestinal disorders have become problems.
  • Japanese Patent Publication 6-10 0 589 Publication
  • Japanese Patent Publication No. 2 7 6 6 Japanese Patent Publication No. 6-312 941
  • Japanese Patent Publication No. 6-6 259 9 Japanese Patent Application No. 63-50981
  • Japanese Patent Publication No. Hei 7—1 3 2 0 95 Japanese Patent Application No. 5-166061 / 55
  • Japanese Patent Publication No. Hei 7-55882 Japanese Patent Application No. 62/134/60) publication
  • 09 3 0 1 1 7 7 JP US Patent NO.
  • the PG I 2 derivative is no specific description or suggestion of having an effect to extend the blood vessels of the eye topically. Further, there is no description that the PGI 2 derivative inhibits the vasoconstriction effect of a physiologically active substance such as ET-1.
  • topical ocular administration may lead to glaucoma, including normal-tension glaucoma due to ocular circulation, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, and retina. There is no description that it is useful for the prevention or treatment of venous occlusion, diabetic retinopathy, choroidal disease secondary to retinal lesions, retinal choroidal disease, eye strain, or myopia associated with eye strain.
  • An object of the present invention is to provide a novel preventive and ameliorating agent for ocular circulation disorders having a strong ocular circulation improving effect and having few side effects such as a decrease in blood pressure. More specifically, it is an object of the present invention to provide a prophylactic and / or ameliorating agent for ocular circulatory dysfunction which acts locally on the eye and has an excellent effect of suppressing or ameliorating vasoconstriction, blood flow reduction and visual impairment due to vasoconstrictors in vivo. Aim.
  • the present inventors have found that the vasodilation possessed by certain PGI 2 derivatives It has been found that the tonicity acts locally on the eye, and that the PGI 2 derivative inhibits the vasoconstriction by ET-1, one of the in vivo vasoconstrictors. Furthermore, they have found that the PGI 2 derivative has the effect of reducing ocular blood flow and visual impairment observed when obstructing ocular circulation, and that the PGI 2 derivative has glaucoma (including normal tension glaucoma). The present invention has been found to be useful for the prevention or improvement of diseases caused by ocular circulatory disorders, and the present invention has been completed.
  • the present invention is as follows.
  • A represents an ethylene group, a vinylene group, or an ethynylene group
  • R has a linear or branched alkyl, alkenyl, or alkynyl group having 4 to 10 carbon atoms, and has a substituent.
  • which may be an aralkyl group, or, prostaglandin I 2 represented by representing) a cycloalkyl group or 3-8-membered ring which may have a substituent
  • An agent for preventing or ameliorating ocular circulation disorders comprising a (PGI 2 ) derivative, a lower alkanol ester thereof, or a pharmacologically acceptable salt thereof.
  • R is 2-methylpentyl, 1-methylhexyl, 2-methylhexyl A 1,1-dimethylpentyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, or a 1,1-dimethyl-3-hexynyl group
  • the prophylactic and / or ameliorating agent for ocular circulation disorder according to the above (1) which is represented by:
  • Ocular circulation disorders include glaucoma (especially normal tension glaucoma), retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetes Any one of the above (1) to (7), which is at least one disease selected from the group consisting of pathologic retinopathy, choroidal disease secondary to retinal lesions, retinal choroidal disease, eye strain and myopia associated with eye strain.
  • the preventive and ameliorating agent for ocular circulation disorder according to 1.
  • An effective amount of a PG I 2 derivative represented by the general formula (I), a lower alkanol ester thereof, or a pharmacologically acceptable salt thereof is administered to prevent and improve ocular circulation disorders. Prevention and improvement of ocular circulatory disorders including giving.
  • FIG. 1 is a graph showing a change over time in blood flow when 0.00001% ophthalmic solution is instilled with respect to a decrease in blood flow in the optic disc due to ET-1 injection in Experimental Example 1.
  • the horizontal axis is the elapsed time (minutes) when the time of instillation of 0.00001% ophthalmic solution is 0, and the vertical axis is the relative optic disc blood flow (100% of the optic disc blood flow at the time of ET-1 injection). %).
  • Each value represents the standard error of the mean (4 cases).
  • FIG. 2 is a graph showing the temporal change in the amplitude of the visual evoked potential when 0.00001% ophthalmic solution is applied to the visual impairment during ET-1 injection in Experimental Example 2.
  • the horizontal axis is the elapsed time (minutes) when the time of instillation of 0.00001% ophthalmic solution is set to 0, and the vertical axis is the relative visual evoked potential when the amplitude of the visual evoked potential at the time of ET-1 injection is 100%. Indicates the amplitude (%). Each value represents the mean soil standard error (the number of cases is 6).
  • PGI 2 derivative used in the present invention examples include beraprost (TBK-100), epoprostenol sodium, 0P-41483, M-19791, Hoe 892, R-59274, CG4203, clinprost, eye
  • a PGI 2 derivative represented by the general formula (I) (hereinafter also referred to as “the present compound”) is preferably exemplified by oral prost, thyloprost, nile prost, carboplastacycline and the like.
  • the direction of the hydroxyl group at the 15-position may be downward (S configuration) or upward (R configuration) with respect to the paper surface as indicated by a wavy line.
  • ⁇ is preferably an ethylene group, a vinylene group or an ethynylene group, particularly preferably a vinylene group.
  • R is preferably a linear or branched alkyl group, alkenyl group or alkynyl group (hereinafter collectively referred to as a chain hydrocarbon group). Among them, as described later, a branched chain hydrocarbon group is preferred. Groups are preferred.
  • the chain hydrocarbon group has 4 to 10 carbon atoms, and preferably 5 to 8 carbon atoms.
  • the straight-chain portion excluding the branch preferably has 5 to 6 carbon atoms. Further, the straight chain portion may have at least one (preferably one) unsaturated double bond or unsaturated triple bond.
  • the branched portion is preferably a methyl group or an ethyl group, particularly preferably a methyl group.
  • Two or more branched portions may be present, and preferably one or two. Further, the two branched portions may be bonded to one carbon atom. Further, the bonding position of the branched portion is preferably the first to third positions of the chain hydrocarbon group, and particularly preferably the first to second positions. In this case, it is preferable that the unsaturated double bond / unsaturated triple bond is present at the 3-position or later.
  • R is a chain hydrocarbon group
  • specific examples include n-butyl group, n-pentyl group, n-hexyl, n-heptyl, n-octyl, n-decyl, 1-methylpentyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylpentyl, 2 —Methylhexyl group, 3-pentenyl group, 1-methyl-3-pentene group, 1-methyl-3-hexenyl group, 1,1-dimethyl-3-pentenyl group, 1,1-dimethyl-3-hexenyl Group, 2-methyl-3-pentenyl group, 2-methyl-3-hexenyl group, 3-pentynyl group, 1-methyl-3-pentynyl group, 1 monomethyl-3-hexynyl group, 2-methyl-3-pentynyl group, 2 —Methyl—3-hexynyl group, 1,1-di
  • chain hydrocarbon groups preferred are 2-methylpentyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylpentyl, 1-methyl-3-pentynyl A 1-methyl-3-hexynyl group; and a 1,1-dimethyl-3-hexynyl group, and more preferably a 1-methyl-3-pentynyl group and a 1-methyl-3-hexynyl group.
  • R may be an aralkyl group which may have a substituent other than a chain hydrocarbon group or a 3- to 8-membered cycloalkyl group which may have a substituent.
  • the aralkyl group in the aralkyl group which may have a substituent is an aralkyl group having 10 or less carbon atoms comprising a phenyl group-containing alkyl group having 4 or less (preferably 1 to 2). preferable.
  • Examples of the 3- to 8-membered cycloalkyl group in the 3- to 8-membered cycloalkyl group which may have a substituent include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. And a cyclopentyl group and a cyclohexyl group are preferred.
  • substituents include an alkyl group (preferably having 4 or less carbon atoms), a methyl halide, and a halogen atom (chlorine, bromine, fluorine, and iodine), and preferably an alkyl group having 1 to 2 carbon atoms and a halogen atom. Is mentioned.
  • R is an aralkyl group ⁇ cycloalkyl group
  • specific examples include (3-methylphenyl) methyl group, (3-chlorophenyl) methyl group, and (3-fluorophenyl Enyl) methyl group, (3-bromophenyl) methyl group, ⁇ (3-trifluoromethyl) phenyl ⁇ methyl group, 1- (3-methylphenyl) ethyl group, 11- (3-chlorophenyl) ethyl group, ⁇ — ⁇ ( 3- (trifluoromethyl) phenyl ⁇ ethyl group, 1- (3-fluorophenyl) ethyl group, 1- (3-bromophenyl) ethyl group, 2- (3-methylphenyl) ethyl group, 2 -— ( 3- (chlorophenyl) ethyl group, 2-((3-trifluoromethyl) phenyl ⁇ ethyl group, 2- (3-fluor
  • Derivatives are particularly preferably included. More preferably, a sodium salt of the compound represented by the formula (II) is used.
  • the present compound has an asymmetric carbon in its structure, there are various stereoisomers and optical isomers, but the PGI 2 derivative used in the present invention includes all of these stereoisomers and optical isomers. Includes isomers and mixtures thereof.
  • the present compound which is included as an active ingredient in the agent for preventing and improving ocular circulation disorders of the present invention, can be produced, for example, by the method described in JP-A-7-330725.
  • This compound can also be used as its lower alkanol ester.
  • the lower alkanol ester of the present compound is an ester formed by reacting the carboxyl group at the 1-position of the present compound with a lower alkanol.
  • Lower alkanol has 4 carbon atoms The following alkanols are preferred, and alkynols having 1 to 2 carbon atoms are particularly preferred.
  • Specific lower alkanol Ichiru for example, methanol, ethanol, n- propanol, i one propano Ichiru, _ n-butanol, i- butanol, t-butanol. 'This compound can also be used as a pharmacologically acceptable salt.
  • Such salts include, for example, inorganic bases (eg, sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.), organic bases (eg, primary amines such as ethanolamine, getylamine, diethanolamine, dicyclohexyl) Salts with basic substances such as amines, secondary amines such as N, N, dibenzylethylenediamine, tertiary amines such as trimethylamine, triethylamine, pyridine, picoline, and triethanolamine).
  • inorganic bases eg, sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.
  • organic bases eg, primary amines such as ethanolamine, getylamine, diethanolamine, dicyclohexyl
  • Salts with basic substances such as amines, secondary amines such as N, N, dibenzylethylenediamine, tertiary amines such as trimethylamine, triethylamine, pyridine, picoline, and triethanol
  • PG I 2 derivative represented by the general formula (I) and their esters and salts include the following compounds.
  • the compound, its lower alkanol ester, or its pharmacologically acceptable salt has an ocular circulation improving effect on mammals such as humans, dogs, dogs, dogs, mice, and rats.
  • Glaucoma including normotensive glaucoma caused by impaired ocular circulation, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetic retinopathy It suggests use as a prophylactic or therapeutic agent for choroidal diseases secondary to retinal lesions, retinal choroidal diseases, eye strain, and diseases caused by ocular circulation disorders such as myopia associated with eye strain.
  • the parenteral administration form When used as a pharmaceutical, it can be administered orally or parenterally.
  • the administration form include oral forms such as tablets, capsules and syrups, liquid injections such as solutions, emulsions and suspensions, external preparations such as ointments (especially ophthalmic ointments), eye drops and the like.
  • the parenteral administration form is exemplified, but considering the effects on other circulatory systems, it is preferably used in a form for topical administration to the eye, and particularly preferably in the form of eye drops or ointment.
  • the pharmacologically acceptable salt of this compound is water-soluble, so it can be easily formulated into ophthalmic solutions, etc., and is more than 10,000 times more stable in aqueous solution than natural PGI 2 , and is extremely clinically It can be a formulation that is easy to handle.
  • the preparation of the above-mentioned administration form can be produced by compounding the present compound with additives required for preparation such as ordinary carriers, excipients, binders, stabilizers and the like, and formulating by conventional means.
  • any pharmaceutical carrier suitable for producing a solid preparation such as an excipient (starch, glucose, fructose, sucrose, etc.), a lubricant (magnesium stearate, etc.) ), Disintegrants (starch, crystalline cellulose, etc.), binders (starch, gum arabic, etc.) and the like, and may be coated with a coating agent (gelatin, sucrose, etc.).
  • a stabilizing agent sodium edetate, etc.
  • a suspending agent such as sodium arabic, carmellose, etc.
  • a flavoring agent such as glucose, etc.
  • a fragrance such as a fragrance, etc.
  • a solvent eg, distilled water for injection
  • a stabilizer eg, sodium edetate
  • a tonicity agent eg, sodium chloride, glycerin, mannite
  • a pH adjusting agent hydroochloric acid, citric acid, sodium hydroxide, etc.
  • a suspending agent methyl cellulose, etc.
  • a solvent physiological saline, purified water, etc.
  • a stabilizer sodium edetate, citric acid, etc.
  • a wetting agent glycerin, etc.
  • an emulsifier for example, a solvent (physiological saline, purified water, etc.), a stabilizer (sodium edetate, citric acid, etc.), a wetting agent (glycerin, etc.), an emulsifier
  • the preparation is an ophthalmic ointment
  • it can be manufactured by appropriately selecting an ointment base (such as serine, lanolin, and plastibase) and a preservative (such as benzalcodium chloride, parabens, and chlorobutanol). it can.
  • an ointment base such as serine, lanolin, and plastibase
  • a preservative such as benzalcodium chloride, parabens, and chlorobutanol
  • the dosage and frequency of administration of the preventive and ameliorating agent for ocular circulatory disorders of the present invention will vary depending on the symptoms, age, body weight, and dosage form.
  • Ophthalmic ointment can be administered several times a day, preferably 1 to 6 times, 1 drop, preferably 1 to 3 drops of a formulation containing ⁇ 0.1 w / v%, preferably 0.0000001 to 0.01 wZv%.
  • a formulation containing 0.00000001 to 0.1 w / w% of the present compound, preferably 0.0000001 to 0.01 w / w% can be applied several times a day, preferably 1 to 6 times. .
  • the compound of the above-mentioned (6) which is a sodium salt of the compound represented by the formula (II) [5 — [(1S, 5R, 6R, 7R) —2-oxa-4,4-difluoro] 7-Hydroxy-1-6-((3S, 4S) —3-Hydroxy-14-methyl-E—1-Nonen-1-6-ynyl ⁇ bicyclo [3.3.0] octane-3-ylidene] sodium pentanoate
  • the aqueous ophthalmic solution of the present invention was prepared according to the following formulation.
  • W 7 This compound (Compound (6)) 0. OOOOlg _ Sodium dihydrogen phosphate O.lg
  • An aqueous ophthalmic solution of the present invention was prepared in the same manner as in Example 1 using the compound of the above (6), which is the sodium salt of the compound of the formula (II), according to the following formulation.
  • the compound of the above [5-[(1S, 5R, 6R, 7R) -2-oxa-1,4,4-difluoro-7-hydroxy-6- ⁇ (3R, 4S) — 3-hydroxy-14-methyl-E-1-nonen-6-ynyl ⁇ bicyclo [3.3.0] octane-3-ylidene] pentanoate] according to the following formulation and the aqueous ophthalmic solution of the present invention was prepared. Prepared.
  • Example 4 An aqueous ophthalmic solution of the present invention was prepared according to the following formulation using the compound of the above (6), which is the sodium salt of the compound represented by the formula (II), as in Example 1 as the present compound.
  • the compound of the above-mentioned (9) [5-[(1S, 5R, 6R, 7R) -2-oxoxa-4,4-difluoro-7-hydroxy-6- ⁇ (3S, 4RS) -3-hydroxy-1
  • Aqueous ophthalmic solution of the present invention was prepared using 4-methyl-E-1-octen-6-ynyl ⁇ bicyclo [3.3.0] octane-13-ylidene] pentanoate according to the following formulation.
  • the compound of the above (5) which is an ester of the compound represented by the formula (II) [5 — [(1S, 5R, 6R, 7R) -2-oxo-4,4-difluoro-7 —Hydroxy-1 6— ⁇ (3 S, 4 S) — 3-Hydroxy-1 4-methyl-E— 1-Nonen-1-6-ynyl ⁇ Bicyclo [3.3.0] octane-1-3-ylidene] ⁇ [Ophthalmic ointment] of the present invention was prepared using the following formula. This compound (Compound (5)) 0. OOOOlg
  • the compound of the above (1) [5 — [(1S, 5R, 6R, 7R) -2—oxa-1,4,4-difluoro-7—hydroxy-6 — ⁇ (3S, 4RS) — 3 —Hydroxy-1-methyl-1-E-1-nonen-1-6-ynyl ⁇ bicyclo [3.3.0] octane-3-ylidene] pentanoic acid Tablets were formed by a conventional method. Sugar coating may be applied as necessary.
  • the compound of the above (10) [5-[(1S, 5R, 6R, 7R) -2-oxa-1,4,4-difluoro-7-hydroxy-6- ⁇ (3R, 4RS) -3-Hydroxy-l-methyl-l-E-l-nonen-6-ynyl ⁇ bicyclo [3.3.0] octane-l_3-ylidene] pentanoic acid] was used as the potassium salt according to the following formula, and an injection was prepared. Prepared.
  • a 0.00001% ophthalmic solution of the present invention was prepared according to Example 1 using the sodium salt of the compound represented by the formula (II) (that is, the compound (6)) as the present compound.
  • the eye on which the drug was instilled was determined so that the average of the initial values was almost the same.
  • 201 drops of 0.00001% ophthalmic solution were applied in one eye to one eye, and 20 ⁇ 1 of saline was applied to the opposite eye as a control eye.
  • Assay ⁇ significant difference test was performed using a paired t-test, c 4 expressed by a significant difference relative to control eyes) Result -
  • Fig. 1 shows the relative blood flow of the optic nerve head (when the initial value is 100%) when the 0.00001% ophthalmic solution is instilled.
  • blood flow 30 minutes after ET-1 injection was reduced by 23% compared to blood flow immediately before ET-1 injection.
  • the blood flow 30 minutes after the injection of ET-1 was 26% lower than the blood flow immediately before the injection of ET-1 and was about the same as the control eye.
  • a significant blood flow increasing effect was observed 30 minutes after instillation as compared with the control eye, and the blood flow was restored to the value before the injection of ET-1.
  • the 0.00001% ophthalmic solution suppressed the decrease in blood flow at the optic disc in the eyes in which ET-1 induced circulatory disturbance, due to the binding to a receptor on the vascular smooth muscle cells of the optic disc. This is thought to be due to the fact that activation of adenylate cyclase increased cyclic AMP, normalized the intracellular calcium concentration increased by ET-1 and suppressed vascular smooth muscle contraction. .
  • the present invention is particularly effective in preventing and improving various diseases caused by ocular circulatory dysfunction by restoring the decrease in blood flow of the optic disc in eyes with circulatory dysfunction caused by ET-1 or the like, especially by instillation. It turns out to be useful.
  • Visual evoked potential is a potential change induced by visual stimulus.
  • electrodes were attached to the visual area. Therefore, it reflects information such as a route for transmitting visual information such as the retina and the optic nerve.
  • diagnosis of optic nerve disease, glaucoma Because of the increasing application to diagnostics and evaluation of progression, the measurement of visual evoked potential is useful as a method for measuring visual impairment in animals that cannot perform subjective tests. It is considered to be.
  • VEP visual evoked potential
  • Midline P (0.5% tropicamide / 0.5% phenylephrine hydrochloride; Santen Pharmaceutical Co., Ltd.
  • 10_ e MET-1 (human, Funakoshi) 101 was injected into the vitreous using a microsyringe.
  • the eye drops prepared in Experimental Example 1 were instilled 20 ⁇ 1 in one eye 2 hours after ET-1 injection, and 201 saline was instilled in the opposite eye as a control eye.
  • VEP was measured using an evoked potential recorder (Neuropack 2, manufactured by Nihon Kohden). Blinks the xenon strobe and measures the potential changes induced by the blinking stimulus before and after ET-1 infusion, 1 to 2 hours after infusion, and 30 minutes and 1 hour after instillation of ophthalmic solution or saline, and thereafter at 1 hour intervals It was measured over time up to 7 hours after instillation.
  • Neuropack 2 manufactured by Nihon Kohden
  • the significant difference test was performed using a paired t-test, and expressed as a significant difference with respect to the change rate of the VEP amplitude of the control eye.
  • FIG. 2 shows the effect of instillation of the test drug 0.00001% ophthalmic solution on the decrease in relative VEP amplitude after ET-1 injection.
  • the amplitude of VEP in control eyes was reduced by 57% 2 hours after ET-1 injection.
  • the amplitude of VEP showed a maximum attenuation of 78% 4 hours after instillation of the saline solution, and a 62% attenuation was observed even after 7 hours.
  • the VEP amplitude of the test drug 0.00001% ophthalmic solution ophthalmic solution ophthalmic solution showed a decrease of 6 ⁇ % 2 hours after injection of ET-1 and a similar decrease of the VE ⁇ amplitude as the control eye. At this time, however, when the test drug 0.00001% ophthalmic solution was instilled, a significant increase in the amplitude of V ⁇ ⁇ was observed from 30 minutes to 3 hours after instillation as compared with the control eyes.
  • the present invention is considered to be useful for improving visual impairment, particularly for improving visual impairment caused by impaired ocular circulation, because V E ⁇ amplitude was increased by the blinking stimulus attenuated by ⁇ -1.
  • the preventive and ameliorating agent for ocular circulation disorders of the present invention includes glaucoma including normotensive glaucoma, retinal pigmentary degeneration, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, and retinal vein occlusion. It is useful for diseases such as retinopathy, diabetic retinopathy, choroidal disease secondary to retinal lesions, retinal choroidal disease associated with systemic disease, eye strain, and myopia associated with eye strain.
  • glaucoma including normotensive glaucoma, retinal pigmentary degeneration, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, and retinal vein occlusion. It is useful for diseases such as retinopathy, diabetic retinopathy, choroidal disease secondary to retinal lesions, retinal choroidal disease associated with systemic disease, eye strain, and myopia associated with eye strain.

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Abstract

Cette invention concerne des médicaments à action préventive et des remèdes destinés aux troubles circulatoires ophtalmiques. Ces médicaments et ces remèdes contiennent des dérivés de prostaglandine I2 représentés par la formule (I), des esters d'alcanoyle inférieurs ou des sels pharmacologiquement acceptables de ces derniers. Dans la formule A représente éthylène, vinylène ou éthynylène; et R représente alkyle, alcényle ou alcynyle C4-10 linéaire ou ramifié, aralkyle facultativement substitué ou cycloalkyle contenant de 3 à 8 éléments facultativement substitués. Ces médicaments sont utiles en tant que remèdes pour des maladies provoquées par des troubles circulatoires ophtalmiques tels que le glaucome (y compris le glaucome avec tension oculaire normale), la dégénérescence des pigments rétiniens, la dégénérescence maculaire, la maladie ischémique du nerf optique, l'iridocyclite, l'embolie rétinienne, la phlébemphraxis rétinienne, la rétinopathie diabétique, les maladies choroïdiennes accompagnant la dégénéréscence rétinienne, la maladie chorio-rétinienne, la fatigue oculaire et la myopie accompagnant la fatigue oculaire, et autres.
PCT/JP1998/004599 1997-10-14 1998-10-12 Medicaments a action preventive et remedes contre les troubles circulatoires ophtalmiques WO1999018970A1 (fr)

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Cited By (3)

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WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
WO2007141898A1 (fr) * 2006-06-02 2007-12-13 Riken Vitamin Co., Ltd. Agent améliorant la tension oculaire
US7618658B2 (en) * 2002-06-13 2009-11-17 Hououdou Co., Ltd. Anti-microbial agent and anti-microbial composition

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JPH03501025A (ja) * 1988-09-06 1991-03-07 フアーマシア・アンド・アツプジヨン・アー・ベー 縁内障または眼圧亢進の治療のためのプロスタグランジン誘導体
JPH07330752A (ja) * 1994-04-11 1995-12-19 Asahi Glass Co Ltd ジフルオロプロスタサイクリン類

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
US7618658B2 (en) * 2002-06-13 2009-11-17 Hououdou Co., Ltd. Anti-microbial agent and anti-microbial composition
WO2007141898A1 (fr) * 2006-06-02 2007-12-13 Riken Vitamin Co., Ltd. Agent améliorant la tension oculaire

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